ABSTRACT (Overall) Untreated HIV infection is generally characterized by a continuous battle between the virus and the host immune response, with billions of new virions and infected cells produced and cleared every day. Treatment with ART eliminates the vast majority of (or potentially all) HIV replication, and plasma viral loads often fall to levels that are undetectable with standard clinical assays. However, certain reservoirs of replication-competent virus persist during therapy. Therefore if ART is stopped then virus can emerge from these reservoirs and rapidly spread, causing renewed progression towards AIDS. The goal of this program project is to gain a better understanding of the factors that cause this viral rebound, and to develop new methods to control or minimize viral rebound following cessation of therapy. We intend to approach this problem by utilizing cutting edge humanized mouse models, coupled with unique viral reagents, including a barcoded HIV swarm, as well as additional novel reagents (chimeric antigen receptors) and vaccine strategies. This program will involve three scientific projects, an administrative core (Core A), and two scientific cores. Projects include 1) ?Defining the causes and consequences of viral rebound?, which will study what factors influence activation of cells to give rise to viral rebound; 2) ?Impact of engineered immune cells on HIV rebound?, which will determine the effect of engineered innate and anamnestic cells on viral rebound; 3) ?Effects of vaccines on formation and clearance of the HIV latent reservoir?, which will determine the effect of vaccination, with either a non-HIV- specific or an HIV-specific vaccine on viral reservoirs and rebound. The two scientific cores will be the Viral Genetics Core (Core B) that will perform sequencing and bioinformatics analysis of barcoded virus for all projects, and the Humanized Mouse Core (Core C), which will perform in vivo manipulations for all projects. Together we hope to define factors contributing to viral rebound, and possibly identify adjunctive therapeutic approaches to provide patients with sustained virologic remissions.